human islet transplantation in brittle type 1 diabetes mellitus. the gragil 2 study.

Conditions: Type 1 Diabetes Mellitus

Summary: this research project is supported by a multicentric network of collaborators whose goal is to assess the efficacy of transplanting allogenic pancreas islets to restore insulin secretion in patients with brittle type 1, insulin-dependent diabetes mellitus and to improve their metabolic control.

the general objective is to demonstrate the beneficial effect of islet allotransplantation in patients with brittle type 1 diabetes with no endogenous insulin secretion, for whom the risk of the spontaneous course of the disease is judged to be worse than the transplantation-related risk. the specific objective is to establish reference data for islet transplantation in non-uremic patients with brittle diabetes, in a multicentric network setting, using the edmonton protocol.

Eligibility criteria:
inclusion criteria: * type 1 diabetes mellitus * disease duration \> 5 years * despite intensive insulin therapy with tight endocrinologist supervision, persistence of the following conditions : hypoglycemia unawareness (\< 54 mg/dl) ; brittleness with at least two episodes of severe hypoglycemia ((defined by the need for assistance to correct the blood glucose level) or ketoacidosis per year , or often enough that the diabetologist judges the frequency to be life-threatening, the risk of transplantation and immunosuppression being judged to be less than the risk of the spontaneous course of uncontrolled diabetes * basal and stimulated plasma c-peptide \< 0.2 ng/ml * creatinine clearance ≥ 50 ml/min/1.73 m2 and proteinuria \< 0.5 g/24h exclusion criteria: * severe cardiovascular disease (recent myocardial infarction, unstable coronaropathy...) * severe systemic infection, including hepatitis c or b viral infection, hiv infection or tuberculosis * past or present neoplasia (with the exception of non melanoma skin cancers) * body weight \> 70 kg in women and bw \> 75 kg in men or bmi \> 26 * stimulated c-peptide ≥ 0.3 ng/ml upon glucagon or arginine stimulation * age \ 65 years * creatinine clearance \< 50 ml/min/1.73 m2 * albuminuria \> 300 mg /24h or proteinuria \> 0.5 g/24h * hemoglobinemia \< 120 g/l in women or \< 130 g/l in men * liver disease (enzymes \> 1.5 n) such as cirrhosis or hepatitis * liver hemangioma * untreated proliferating diabetic retinopathy * pregnancy, lactation, pregnancy project or absence of efficient contraception * previous transplantation or immunization as judged by anti-hla antibodies (\> 20%) * insulin needs \> 0.7 iu/kg/d or \> 50 iu * hba1c \> 12 % * any medical condition needing the chronic use of steroids * addison disease * any hemostasis disorder needing a prolonged treatment with anticoagulation drugs. low-dose aspirin is permitted. coagulation disorders contraindicating the procedure, such as platelet count \< 100000/mm3. * serious life-threatening disease * medical or surgical history potentially influencing the absorption, distribution, metabolism and clearance of drugs * uncontrolled hypercholesterolemia (\> 350 mg/dl, 9.1 mmol/l) or hypertriglyceridemia (\> 500 mg/dl, 5.6 mmol/l) * leukocytes \< 4500/mm3, neutrophils \< 2000/mm3, platelets \< 100000/mm3 * any medical or psychosocial condition susceptible to interfere with the study, such as drug abuse or recent alcohol abuse * poor therapeutic observance * failure to communicate or cooperate with the investigator

Keywords: islet transplantation brittle diabetes severe hypoglycemia type 1 diabetes mellitus